Continuing studies of the mechanisms basic to the destruction of blood cells in man, the principal investigator is concentrating upon immunohemolytic anemias. In most of these, red cell destruction is mediated by an immunologic mechanism in which lysis is extracellular and secondary to the adherence to macrophages. Red cells with gamma G (of the gamma l or gamma 3 subclasses) attached to their membranes adhere on contact to membrane "receptors" of mononuclear cells. These "receptors" react mainly with the CH3 region of the Fc fragment and with a part of the adjacent F(ab)2 fragment. This gamma G-mediated cell-cell attachment is: very stable; does not involve complement, properdin, or any immunoglobulin other than gamma G1 and gamma G3; and seldom progresses to phagocytic ingestion (unlike inter-species reactions). Monocytes and macrophages respond to gamma G-coated cells by extending long (10-20 micron) aborizing processes which invaginate and enmesh the red cells, with fusion to their membranes. Certain lymphocytes also bind gamma G-coated red cells, but fewer cells become attached, the processes are short and non-branching, and fusion is undetectable. The studies planned are concerned with assessing the actual physiological role of gamma G-mediated binding of red cells, and of other cells, to macrophages. Mononuclear binding is a feature of Coombs-positive hemolytic anemias, but its pathogenic importance remains undetermined. As immunity in man often relies upon nonlytic "containment" mechanisms -often without destruction of offending cells, efforts will be made to determine whether chronic, endemic resistance (as to malaria, Bartonellosis protozoal infections, and granulomatous disorders in general) is the consequence of this gamma G-mediated cell-cell interactions will be examined in experimental systems freed of the many artifacts which flaw prior studies: these include use of the 3-dimensional fluid system, use of cell populations of homogeneous structure separated by non-injurious techniques, and emphasis upon kinetics and morphology.